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Alzheimer's Genetic Suspect Comes Forward

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TORONTO -- A second gene as a possible accessory in the development of late-onset Alzheimer's disease has been identified by an international team of researchers.

TORONTO, Jan. 15 -- A second gene as a possible accessory in the development of late-onset Alzheimer's disease has been identified by an international team of researchers.

Inherited variants of the gene, called SORL1, short for sortilin-related receptor 1, may be indirectly involved in the abnormal production and deposition in the brain of beta-amyloid plaques, reported the researchers online in Nature Genetics.

"Taken together, our results suggest that genetic and possibly environmentally specified changes in SORL1 expression or function are causally linked to the pathogenesis of Alzheimer disease and have a modest effect on risk for this disease," wrote Peter St. George-Hyslop, M.D., D.Sc., of the University of Toronto, and colleagues.

If SORL1 is indeed a key player in the development of Alzheimer's disease, it will join the gene that encodes for apolipoprotein E (ApoE) as a target for research into the origin of Alzheimer's disease and potential therapeutic agents.

SORL1 normally directs the cellular trafficking of the amyloid precursor protein, or APP, said Dr. St. George-Hyslop, in a briefing.

"This SORL1 protein actually acts as a regulator for how APP is sent around the cell," he said. "We found that when SORL1 is present, it keeps APP directed away from the sites in the cell where APP is normally degraded into the neurotoxic amyloid-beta peptide. When SORL1 is absent, or defective, it then allows APP to traffic into these forbidden regions of the cell, and therefore allows APP to be degraded into the neurotoxic A?-peptide fragments."

While it's known that certain alleles of Apo-e E are associated with either enhanced risk for (ApoE-4) Alzheimer's or protection from the disease (ApoE-2), the investigators have yet to determine which genetic variants of SORL1 may be at work in the pathology of the disease, they acknowledged.

"Other groups have previously shown that the levels of SORL1 are reduced in brain cells of patients with Alzheimer's disease, and what we found is that carriers of some of the variants associated with Alzheimer's disease also expressed lower levels of SORL1, Dr. St. George-Hyslop said. "So we believe the genetic defects are likely to impede the function of SORL1, resulting in more APP being sent to places in the cell where it's degraded into A? peptide."

The investigators based their findings on data from more than 6,000 people in North America, Europe, and Asia. The data came from several primary sources: DNA from families with two or more members currently living with Alzheimer's disease, and two data sets from the MIRAGE (Multi-Institutional Research in Alzheimer's Genetic Epidemiology) database. The MIRAGE data included information on siblings who were discordant for the disease, and data on African-American families, including families with and without a history of Alzheimer's.

The authors also conducted a case-control study, comparing genetics among people who met research and clinical criteria for probable Alzheimer's disease with matched controls, including data on more than 400 people with autopsy-confirmed disease.

"One of the main characteristics of these families and these individuals is that for the affected people the average age of onset was in the 70s, so these are not early-onset cases, these were the more typical late-onset form," commented co-author Richard Mayeux, M.D., M.Sc., of Columbia University in New York.

They identified two clusters of SORL1 variants that were significantly over-expressed among Alzheimer's disease patients.

The investigators also provided preliminary evidence from in vitro studies showing A-beta peptide production was increased in cell when SORL1 levels were reduced, suggesting that crippled variants of the gene could allow the abnormal production of amyloid protein that is a hallmark of the neurodegenerative process underlying Alzheimer's.

Their findings implied that there are several different Alzheimer's disease-associated allelic variants in distinct regions of SORL1 in different populations, and that the variants may occur in a region of the gene controlling where in cells or in what types of tissues the gene products are expressed, the authors wrote.

The next steps, Dr. St. George Hyslop said, are to replicate the findings in larger populations, to determine the predictive value of the disease-causing variants, and to see whether the finding might lead to new methods for diagnosing and treating Alzheimer's disease.

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